Process for preparing a piperidine derivative

ABSTRACT

A piperidine derivative, which can be used as an intermediate for pharmaceuticals such as paroxetine useful as antidepressants, represented by the general formula (I):                    
     wherein R 1  is hydrogen atom, benzyloxycarbonyl group or tert-butoxycarbonyl group; R 2  is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or —CO 2 R 7  group in which R 7  is an alkyl group having 1 to 5 carbon atoms, and Z is methylene group or carbonyl group, with proviso that, (A) when R 1  is benzyloxycarbonyl group or tert-butoxycarbonyl group, then R 2  is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position or (3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group; or (B) when R 1  is hydrogen atom and Z is carbonyl group, then R 2  is carboxyl group or —CO 2 R 7  group (R 7  is as defined above); or (C) when R 1  is hydrogen atom and Z is methylene group, then R 2  is hydroxymethyl group.

This application is a divisional of application Ser. No. 09/695,383,filed on Oct. 25, 2000, now U.S. Pat. No. 6,610,851 which is aDivisional of Ser. No. 09/306,411 filed May 6, 1999, now abandoned,which is a Divisional of Ser. No. 08/871,948 filed Jun. 10, 1997, nowabandoned, the entire contents of which are hereby incorporated byreference and for which priority is claimed under 35 U.S.C. §120; andthis application claims priority of Application No. 8-175893, 8-294585,8-303838, 8-326177 and 9-50980 filed in Japan on Jun. 13, 1996, Oct. 15,1996, Oct. 29, 1996, Nov. 20, 1996, and Feb. 18, 1997, respectivelyunder 35 U.S.C. §119.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a piperidine derivative and a processfor preparing the same More particularly, the present invention relatesto a piperidine derivative useful as an intermediate for pharmaceuticalssuch as paroxetine and the like which are useful, for example, as anantidepressant.

2. Discussion of the Related Art

In general, paroxetine useful as an antidepressant is prepared by theprocesses described, for example, in Japanese Unexamined PatentPublication No. 7-138228 and Japanese Examined Patent Publication No.59-46216.

However, these processes have the drawback that, upon deprotection ofN-methyl group, complicated procedures such as hydrolysis after thetransformation of N-methyl group to carbamate group are required.

In addition, there is disclosed a process for preparing paroxetine usingan amidomalonic acid ester derivative as a starting material in, forexample, Japanese Unexamined Patent Publication No. 7-138228. However,the amidomalonic acid ester derivative is not in general commerciallyavailable. Therefore, there necessitates troublesome procedures suchthat the amidomalonic acid ester derivative should be previouslyprepared before using.

An object of the present invention is to provide a compound useful as anintermediate for preparing paroxetine and a process for simply andindustrially preparing the compound.

These and other objects of the present invention will be apparent fromthe following description.

SUMMARY OF THE INVENTION

Specifically, the present invention is concerned with the following:

(1) A piperidine derivative represented by the general formula (I):

wherein R¹ is hydrogen atom, benzyloxycarbonyl group ortert-butoxycarbonyl group; R² is hydroxymethyl group, analkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbonatoms, phenylsulfonyloxymethyl group which may have methyl group at the4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or—CO₂R⁷ group in which R⁷ is an alkyl group having 1 to 5 carbon atoms,and Z is methylene group or carbonyl group, with proviso that,

(A) when R¹ is benzyloxycarbonyl group or tert-butoxycarbonyl group,then R² is hydroxymethyl group, an alkylsulfonyloxymethyl group havingan alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl groupwhich may have methyl group at the 4-position or(3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group; or

(B) when R¹ is hydrogen atom and Z is carbonyl group, then R² iscarboxyl group or —CO₂R⁷ group (R⁷ is as defined above); or

(C) when R¹ is hydrogen atom and Z is methylene group, then R² ishydroxymethyl group;

(2) The piperidine derivative described in the above item (1), whereinthe piperidine derivative is at least one member selected from(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidine,(3SR,4RS)-trans-1-benzyloxy-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, and(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one;

(3) The piperidine derivative described in the above item (1), whereinR¹ is tert-butoxycarbonyl group or benzyloxycarbonyl group, R² is agroup represented by the formula:

and Z is methylene group in the general formula (I);

(4) A method for preparing a piperidine derivative represented by thegeneral formula (VII);

wherein R³ is benzyl group or tert-butyl group, comprising the steps of:

reacting (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidinerepresented by the formula (II):

with a protecting reagent represented by the general formula (III):

wherein R³ is as defined above; and Y is a chlorine atom ortert-butoxycarbonyloxy group, with proviso that

(A) when R³ is benzyl group, then Y is a chlorine atom,

(B) when R³ is tert-butyl group, then Y is tert-butoxycarbonyloxy group,

to give a carbamate compound represented by the general formula (IV):

wherein R³ is as defined above;

reacting the carbamate compound with a sulfonic acid chloriderepresented by the general formula (V):

wherein R⁴ is an alkyl group having 1 to 2 carbon atoms or a phenylgroup which may have methyl group at the 4-position, to give a sulfonicacid ester represented by the general formula (VI):

wherein R³ and R⁴ are as defined above;

reacting the sulfonic acid ester with 3,4-methylenedioxyphenol underbasic conditions;

(5) A method for preparing(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine representedby the formula (II):

comprising the steps of:

optically resolving(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, to give(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one represented bythe formula (VIII):

and reducing the (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidinewith a metal hydride compound;

(6) A method for preparing(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine representedby the formula (II):

comprising the step of optically resolving(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine;

(7) A method for preparing(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine representedby the formula (II):

comprising the steps of:

transforming(±)-cis,trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-onerepresented by the general formula (IX):

wherein R⁵ is an alkyl group having 1 to 4 carbon atoms; in the presenceof a base, to give(4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one;

reducing the(4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-one witha metal hydride compound, to give(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine; and

optically resolving the(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine;

(8) A method for preparing(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidinecomprising the step of catalytically reducing(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,to deprotect the benzyloxycarbonyl group;

(9) A method for preparing a hydrochloride of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidinecomprising the steps of:

catalytically reducing(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,to deprotect the benzyloxycarbonyl group, to give(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine;and

treating the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinewith hydrogen chloride;

(10) The method described in the above item (9), wherein the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidineis treated with hydrogen chloride in isopropanol;

(11) A method for preparing a hydrochloride of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidinecomprising the step of treating(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinewith hydrogen chloride;

(12) The method described in the above item (11), wherein the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidineis treated with hydrogen chloride in isopropanol;

(13) A method for preparing a hydrochloride of (3S,4R)-trans-4-(4-fluorophenyl )-3- [(3,4-methylenedioxyphenyl)oxymethyl]piperidinecontaining isopropanol, comprising the step of treating the isopropanolsolution of a hydrochloride of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidineprepared by a method described in the above item (10) or item (12) withactive carbon, to remove impurities; and

(14) A method for preparing an anhydrous hydrochloride of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehaving an isopropanol content of 0.1 to 5% by weight, comprising thesteps of:

allowing precipitation of crystals of a hydrochloride of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinefrom the isopropanol solution of the hydrochloride of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidineprepared by a method described in the above item (10), item (12), oritem (13); and

drying the crystals under a reduced pressure at a temperature of from80° to 110° C.

DETAILED DESCRIPTION OF THE INVENTION

As described above, the piperidine derivative of the present inventionis a compound represented by the general formula (I):

wherein R¹ is hydrogen atom, benzyloxycarbonyl group ortert-butoxycarbonyl group; R² is hydroxymethyl group, analkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbonatoms, phenylsulfonyloxymethyl group which may have methyl group at the4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or—CO₂R⁷ group in which R⁷ is an alkyl group having 1 to 5 carbon atoms,and Z is methylene group or carbonyl group, with proviso that,

(A) when R¹ is benzyloxycarbonyl group or tert-butoxycarbonyl group,then R² is hydroxymethyl group, an alkylsulfonyloxymethyl group havingan alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl groupwhich may have methyl group at the 4-position or(3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group;

(B) when R¹ is hydrogen atom and Z is carbonyl group, then R² iscarboxyl group or —CO₂R⁷ group (R⁷ is as defined above); and

(C) when R¹ is hydrogen atom and Z is methylene group, then R² ishydroxymethyl group.

In the general formula (I), R¹ is hydrogen atom, benzyloxycarbonyl groupor tert-butoxycarbonyl group. R² is hydroxymethyl group, analkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbonatoms, phenylsulfonyloxymethyl group which may have methyl group at the4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or—CO₂R⁷ group in which R⁷ is as defined above. Z is methylene group orcarbonyl group.

(A) When R¹ is benzyloxycarbonyl group or tert-butoxycarbonyl group,then R² is hydroxymethyl group, an alkylsulfonyloxymethyl group havingan alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl groupwhich may have methyl group at the 4-position or(3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group.

(B) When R¹ is hydrogen atom and Z is carbonyl group, then R² iscarboxyl group or —CO₂R⁷ group (R⁷ is as defined above).

(C) When R¹ is hydrogen atom and Z is methylene group, R² ishydroxymethyl group.

In the general formula (I),

(A) when R¹ is benzyloxycarbonyl group or tert-butoxycarbonyl group,then R² is hydroxymethyl group, an alkylsulfonyloxymethyl group havingan alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl groupwhich may have methyl group at the 4-position or(3,4-methylenedioxyphenyl)oxymethyl group, and Z is methylene group; and

(C) when R¹ is hydrogen atom and Z is methylene group,

then R² is hydroxymethyl group, there can be cited as the specificexamples of the piperidine derivative represented by the general formula(I), for instance,(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(p-toluylsulfonyloxymethyl)piperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,and(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

In the general formula (I), when R¹ is hydrogen atom and Z is carbonylgroup, and R² is carboxyl group or —CO₂R⁷ group, in which R⁷ is asdefined above, examples of the piperidine derivatives represented by thegeneral formula (I) include(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one,(±)-trans-4-(4-fluorophenyl)-5-ethoxycarbonylpiperidin-2-one,(±)-trans-4-(4-fluorophenyl)-5-propoxycarbonylpiperidin-2-one,(±)-trans-4-(4-fluorophenyl)-5-isopropoxycarbonylpiperidin-2-one,(±)-trans-4-(4-fluorophenyl)-5-butoxycarbonylpiperidin-2-one,(±)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one,(±)-cis-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one,(±)-cis-4-(4-fluorophenyl)-5-ethoxycarbonylpiperidin-2-one,(±)-cis-4-(4-fluorophenyl)-5-propoxycarbonylpiperidin-2-one,(±)-cis-4-(4-fluorophenyl)-5-isopropoxycarbonylpiperidin-2-one,(±)-cis-4-(4-fluorophenyl)-5-butoxycarbonylpiperidin-2-one, and(±)-cis-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Among the above piperidine derivatives, there can be particularlypreferably used in the present invention, at least one member selectedfrom(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine, (3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3SR,4RS)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, and(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

As the starting material for the piperidine derivative represented bythe general formula (I), 4-fluorobenzaldehyde can be used.

The above 4-fluorobenzaldehyde is reacted with an acetic acid esterrepresented by the general formula:

CH₃COOR⁵,

wherein R⁵ is an alkyl group having 1 to 4 carbon atoms to give a4-fluorocinnamic acid ester. A cyanoacetic acid ester represented by thegeneral formula:

NC—CH₂—CO₂—R⁶,

wherein R⁶ is an alkyl group having 1 to 4 carbon atoms is reacted withthe resulting 4-fluorocinnamic acid ester to give a glutaric acid esterderivative represented by the general formula (X):

wherein R⁵ and R⁶ are as defined above. Then, the resulting glutaricacid ester derivative can be reduced to give (±)-cis,trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one representedby the general formula (IX):

wherein R⁵ is as defined above.

The reduction is preferably catalytic hydrogenation, and the reactionconditions are not limited to specified ones. When the catalytichydrogenation is performed, for example, a conventional catalytichydrogenation conditions can be employed where cyano group of theglutaric acid ester derivative represented by the general formula (X) iscatalytically hydrogenated to aminomethyl group. In this case, as thecatalyst, for example, Raney cobalt, Raney nickel, palladium-carbon,platinum-carbon and the like can be used. As a solvent, there can becited, for instance, hydrocarbon solvents such as toluene, estersolvents such as ethyl acetate, ether solvents such as tetrahydrofuran(THF), alcohol solvents such as methanol, and a mixture thereof. Thereaction temperature can be usually within a range of room temperatureto 150° C., and the hydrogen pressure can be, for example, within arange of 0.5 to 150 kgf/cm². Upon reaction, starting materialscontaining the compound represented by the general formula (X) can beintroduced in the reaction vessel at a time, or the compound representedby the general formula (X) can be added to the reaction system underpressure.

The compound (±)-cis,trans-4-(4-fluorophenyl)-5-alkyloxycarbonylpiperidin-2-one representedby the general formula (IX) includes a cis-isomer and a trans-isomer asmain components. In order to obtain the trans-isomer and the cis-isomerfrom the mixture separately thereof, there can be employed a usualmethod for the separation of compounds, such as utilizing the solubilitydifference in a solvent, and a conventional column separation fororganic compounds. The cis-isomer can be converted into the trans-isomerin the presence of a base. Also, the cis-isomer can be converted intothe trans-isomer in the form of an acid, for example, by alkalinehydrolysis.

When the above-mentioned isomerization of the (±)-cis, trans esters iscarried out, for example, by using a sodium alkoxide as a catalyst toobtain crystals, the trans-isomer can be preferentially obtained in theform of an ester.

Also, when (±)-cis, trans-esters are heated to reflux using sodiumhydroxide in an alcohol or in water, the cis-ester is presumably firsttransformed into the trans-ester and hydrolyzed to give a trans-acid.

The (±)-cis,trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-onerepresented by the general formula (IX) can be converted into anoptically active trans-carboxylic acid or its ester by transforming theabove compound into a trans-carboxylic acid ester in the same manner asthe above and hydrolyzing its ester portion using, for example, anenzyme, or by transforming the above compound into a trans-carboxylicacid and asymmetrically esterifying its carboxylic acid portion using anenzyme.

Also, the above racemic trans-carboxylic acid can be resolved into anoptically active trans-carboxylic acid by a usual method for preparing adiastereomer derivative, for example, by a method comprising preparing asalt of the above trans-carboxylic acid and an optically active amine,and separating the salt therefrom as crystals.

More specifically, the optical resolution of (±)-trans-carboxylic acid,that is, (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one,can be carried out usually in a solvent in the presence of an opticallyactive amine.

Representative examples of the optically active amines include compoundsdisclosed, for example, in Japanese Unexamined Patent Publication No.6-116214. More particularly, there can be cited, for instance,R-(+)-N-(4-hydroxyphenylmethyl)phenylmethylamine, and the like.

It is desired that the amount of the optically active amine to be usedis 0.5 to 1.2 moles, preferably 0.6 to 1.1 moles per 1 mole of(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Examples of the solvents include alcohols such as methanol, ethanol,esters such as ethyl acetate, and the like. Those solvents can be usedalone or in admixture thereof. If necessary, those solvents can be usedin admixture with water.

The (4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one and theoptically active amine can be dissolved in the solvent, mixed andallowed to stand or stirred to optically resolve the(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

At this stage, it is desired that the temperature of the mixture isusually −10° to 120° C., preferably 10° to 90° C.

After the completion of the optical resolution, the precipitatedcrystals of the salts are filtered and the resulting crystals aredegraded under acidic or alkaline conditions.

When the resulting crystals of the salts are degraded under alkalineconditions, the crystals are treated with alkaline such as sodiumhydroxide or the like in the presence of water, and optically activeamine is extracted from its aqueous layer with an organic solvent.Thereafter, the alkaline aqueous solution is made acidic to givecrystals of (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Also, when the resulting crystals of the salts are degraded under acidicconditions, the crystals are treated with acidic aqueous solution suchas sulfuric acid, hydrochloric acid or the like to give an aimedcrystalline (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.The optically active amine can be recovered from the remaining acidicaqueous solution by neutralizing the acidic aqueous solution e.g. withsodium hydroxide and extracting with an organic solvent.

The resulting crystals can be filtered and dried for use in the nextreduction reaction.

The (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one can bereduced to give(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine representedby the formula (II):

Upon the reduction reaction, a metal hydride compound (reducing agent)such as diborane, borane complex, boron hydride compound generated fromsodium boron hydride in situ, or aluminum hydride compound such asaluminum hydride, diisobutylaluminum hydride or lithium aluminum hydridecan be used. It is desired that the amount of the metal hydride compoundto be used is usually 6 to 12 equivalents as an active hydride per 1equivalent of the(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one. There can beemployed conventional reducing conditions where a carboxylic acid isreduced to a primary alcohol That is, as a reaction solvent, there canbe employed, for example, an ether solvent such as tetrahydrofuran(THF), and a mixed solvent of the ether solvent and a hydrocarbonsolvent such as toluene. The reaction temperature can be, for example,within a range of ordinary temperature to 100° C. Upon reaction, forexample, when the aluminum hydride compound is used, the reaction isdesirably carried out by adding dropwise the(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one thereto.

Alternatively,(4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-oneobtained by isomerizing (±)-cis,trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidin-2-one represented bythe general formula (IX) in the presence of a base can be reduced with ametal hydride reducing agent to give(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.Thereafter, the(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine can beoptically resolved with an optically active organic acid to give anoptically active compound represented by the formula (II).

As the metal hydride reducing agent, there can be exemplified those usedfor reducing the(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

As the optically active organic acid, there can be used,o-chlorotartranilic acid described in J. Org. Chem., 33, 3993 (1968),and the like.

As the conditions such as the amount of the optically active acid to beused, and kinds of the solvent used for resolution and the amountthereof, those used for the optical resolution of the(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one can beemployed. In addition, as a solvent, water or a mixture of water andacetone can be used.

From (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine thusobtained represented by the formula (II), the piperidine derivativerepresented by the general formula (I) of the present invention where Zrepresents methylene group can be obtained as follows:

First, a process for preparing the piperidine derivative represented bythe general formula (I) wherein R¹ is benzyloxycarbonyl group and Z ismethylene group is explained.

The compound (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidinerepresented by the formula (II) can be reacted with a protective reagentrepresented by the general formula (III):

wherein R³ is benzyl group and Y is chlorine atom, to give a carbamatecompound represented by the general formula (IV):

wherein R³ is benzyl group.

The above reaction can be carried out, for example, by reacting(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine with theprotective reagent represented by the general formula (III) in thepresence of a base such as an aqueous sodium bicarbonate solution, butthis process does not limit the scope of the present invention.

The carbamate compound represented by the general formula (IV) can bereacted with an organosulfonic acid chloride represented by the generalformula (V):

wherein R⁴ is an alkyl group having 1 to 2 carbon atoms or phenyl groupwhich may have methyl group at the 4-position, for example, in thepresence of an acid acceptor such as triethylamine, to give anorganosulfonic acid ester represented by the general formula (VI):

wherein R³ is benzyl group, and R⁴ is methyl group, ethyl group, phenylgroup or 4-methylphenyl group.

More specifically, for example, the carbamate compound represented bythe general formula (IV) can be reacted with methanesulfonyl chloride inthe presence of the acid acceptor to give(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidinerepresented by the general formula (I), wherein R¹ is benzyloxycarbonylgroup, R² is methylsulfonyloxymethyl group, and Z is methylene group.

In addition, for example, the carbamate compound represented by thegeneral formula (IV) can be reacted with ethanesulfonyl chloride,benzenesulfonyl chloride or p-toluenesulfonyl chloride in the presenceof the acid acceptor to give(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-ethylsulfonyloxymethylpiperidine,(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-phenylsulfonyloxymethylpiperidineor(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-(4-methylphenyl)sulfonyloxymethylpiperidinerepresented by the general formula (VI), wherein R³ is benzyl group andR⁴ is methyl group, phenyl group or 4-methylphenyl group (toluyl group),respectively.

Further, the organosulfonic acid ester represented by the generalformula (VI) can be reacted with 3,4-methylenedioxyphenol in thepresence of a base to give(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinerepresented by the general formula (VII):

wherein R³ is benzyl group, which can also be represented by the generalformula (I), wherein R¹ is benzyloxycarbonyl group, R² is3,4-methylenedioxyphenyloxymethyl group, and Z is methylene group.

Next, a process for preparing the piperidine derivative represented bythe general formula (I) wherein R¹ is tert-butoxycarbonyl group and Z ismethylene group is explained.

When (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidinerepresented by the formula (II) is reacted with di-tert-butyldicarbonate as a protecting reagent for aminoic nitrogen, it ispreferable that 1 to 2 moles of di-tert-butyl dicarbonate is usuallyused per 1 mole of(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Upon the reaction, a solvent which is unreactive to the(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine anddi-tert-butyl dicarbonate can be used.

Examples of the solvent include hydrocarbon solvents represented bytoluene, ether solvents represented by tetrahydrofuran, ketone solventsrepresented by methyl isobutyl ketone, and ester solvents represented byethyl acetate. Those solvents can be usually used alone or in admixturethereof.

The amount of the solvent to be used is not specified but preferably inthe range such that the total amount of the(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine anddi-tert-butyl dicarbonate is usually 20 to 100 parts by weight basedupon 100 parts by weight of the solvent.

Upon the reaction, a catalyst can be used if necessary. As the catalyst,there can be cited, for example, organic basic catalysts such astertiary amines such as triethylamine.

The reaction temperature is not limited to specified ones but can beusually within a range of around 0° C. to a boiling point of thesolvent.

The reaction atmosphere is not limited to specified ones, but thereaction can be usually carried out in an ambient atmosphere or in aninert gas such as nitrogen gas.

As a result of the reaction, there can be obtained the carbamatecompound represented by the general formula (IV) wherein R³ istert-butyl group.

Then, the resulting carbamate compound represented by the generalformula (IV) is reacted with organosulfonic acid chloride represented bythe general formula (V).

It is desired that the reaction of the carbamate compound represented bythe general formula (IV) with the organosulfonic acid chloriderepresented by the general formula (V) is usually carried out under thecondition such that 0.95 to 1.2 moles of the organosulfonic acidchloride represented by the general formula (V) is used per 1 mole ofthe starting material(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Upon the reaction of the carbamate compound represented by the generalformula (IV) with the organosulfonic acid chloride represented by thegeneral formula (V), the reaction conditions, more specifically,solvent, catalyst, reaction temperature and reaction atmosphere can bethe same as those for the reaction of(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine representedby the formula (II) and di-tert-butyl dicarbonate.

In the present invention, after the completion of the reaction of(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine representedby the formula (II) and di-tert-butyl dicarbonate, the successivereaction can be achieved by adding the organosulfonic acid chloriderepresented by the general formula (V) and an acid acceptor to thereaction mixture if necessary after the removal of the azeotropic waterfrom the reaction mixture.

Thus, there is obtained a carbamate compound represented by the generalformula (VI), wherein R³ is benzyl group or tert-butyl group.

Then, the organosulfonic acid ester represented by the general formula(VI) is reacted with 3,4-methylenedioxyphenol in the presence of a base.

It is desired that the amount of 3,4-methylenedioxyphenol to be used isusually 1 to 3 moles or so per 1 mole of the organosulfonic acid esterrepresented by the general formula (VI).

As a reaction solvent to be used for reacting the organosulfonic acidester represented by the general formula (VI) with3,4-methylenedioxyphenol, there can be cited, for example, lower alcoholsolvents having 1 to 4 carbon atoms, polar organic solvents such asamide solvents such as dimethylformamide, dimethylacetamide,N-methylpyrrolidone, and dimethyl sulfoxide, and hydrocarbon solventssuch as toluene. Those solvents can be usually used alone or inadmixture thereof.

The amount of the solvent to be used is not limited to specified onesbut is preferably such that the total amount of the organosulfonic acidester represented by the general formula (VI) and3,4-methylenedioxyphenol is usually 20 to 100 parts by weight, basedupon 100 parts by weight of the solvent.

As the base, there can be cited, for example, sodium hydride, sodiummethoxide, sodium amide, potassium tert-butoxide, sodium hydroxide andsodium carbonate.

It is preferable that the amount of the base to be used is usually 0.8to 1 mole per 1 mole of 3,4-methylenedioxyphenol.

The reaction temperature can be usually within a range of ordinarytemperature to the boiling point of the solvent. The reaction can beperformed under pressure if necessary.

The reaction atmosphere is not limited to specified ones, but thereaction can be usually carried out in an ambient atmosphere or in aninert gas such as nitrogen gas.

The piperidine derivative(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinethus obtained, represented by the general formula (VII), wherein R³ isbenzyl group, can be catalytically hydrogenolyzed to deprotect aprotecting group, i.e. benzyloxycarbonyl group. The deprotection of thebenzyloxycarbonyl group can be carried out, for example, as follows:

The(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidineis dissolved in a solvent and the reaction can be carried out bystirring in hydrogen gas atmosphere in the presence of a catalyst.

As the catalyst, there can be cited, for instance, palladium-carbon, andthe like. It is desired that the amount of the catalyst is usually 1 to10 parts by weight or so based upon 100 parts by weight of the(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

As the solvent, there can be cited, for instance, hydrocarbon solventssuch as toluene, ether solvents such as tetrahydrofuran, alcoholsolvents such as methanol, and a mixture thereof.

The reaction temperature can be usually within a range of ordinarytemperature to 100° C.

The pressure of hydrogen gas to be introduced in the solution is notlimited to specified ones but can be usually ordinary atmosphericpressure to around 20 kgf/cm². It is desired that the amount of hydrogengas to be introduced in the solution is usually at least 1 mole per 1mole of the(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine.

The reaction time is not limited to specified ones but can be a timeuntil the completion of the reaction. The completion of the reaction canbe monitored, for example, by chromatography and can be a point at whichthe(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinedisappears.

Thus,(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidineis obtained.

After(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidineis catalytically hydrogenolyzed to deprotect benzyloxycarbonyl group,hydrogen chloride can be added thereto to give(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride. When hydrogen chloride is reacted on the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidinein a nonaqueous anhydrous solvent, anhydrous(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride is obtained, which is useful as an antidepressant.

As a method for preparing anhydrous hydrochloride of the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinefrom the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,there can be employed, for example, the following method.

The(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidineis first dissolved in a nonaqueous solvent.

As the non-aqueous solvent, there can be cited, for instance,hydrocarbon solvents such as toluene, ester solvents such as ethylacetate, ether solvents such as tetrahydrofuran, halogenated solventssuch as dichloromethane, alcohol solvents such as ethanol andisopropanol, and a mixture thereof.

Then, hydrogen chloride gas is introduced in the resulting solution. Theuse of dry hydrogen chloride gas is preferable from the viewpoint thatthe incorporation of moisture in the reaction system is avoided. In thepresent invention, a nonaqueous solvent containing hydrogen chloride init can be added to the solution.

It is desired that the amount of hydrogen chloride to be introduced inthe solution is usually at least 1 mole per 1 mole of the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

The reaction temperature can be usually within a range of ordinarytemperature to the boiling point of the solvent.

The reaction time is not limited to specified ones but can be a timeuntil the completion of the reaction. The completion of the reaction canbe a point at which the weight of absorbed hydrogen chloride reaches arequired amount.

Next, the deprotection of tert-butoxycarbonyl group of the(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidinerepresented by the general formula (VII), wherein R³ is tert-butyl groupcan be carried out by reacting hydrogen chloride on(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinein isopropanol to give(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride. This reaction is a reaction for deprotectingtert-butoxycarbonyl group.

The amount of(3S,4R)-trans-l-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidineto be mixed with isopropanol is not limited to specified ones, butusually the amount is preferably 5 to 50 parts by weight based upon 100parts by weight of the isopropanol.

It is desired that the amount of hydrogen chloride to react on(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidineis usually 1 to 5 moles per 1 mole of(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

In the present invention, for example, other organic solvent and organicacid may be conveniently added thereto in an amount so as not to impairthe object of the present invention.

As the method for reacting hydrogen chloride thereon, there can becited, for instance, a method of first dissolving hydrogen chloride inisopropanol, and adding the(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidinethereto while stirring, a method of introducing hydrogen chloride gasinto a solution obtained by dissolving the(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidinein isopropanol, or a method of adding a solution obtained by dissolvinghydrogen chloride gas in isopropanol to the above(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinewhile stirring, and the like.

The temperature when hydrogen chloride is reacted thereon variesdepending upon the amount of hydrogen chloride used and is usuallywithin a range of ordinary temperature to the boiling point ofisopropanol when the amount of hydrogen chloride is within a range of 1to 2 mole per 1 mole of the(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

When the hydrogen chloride is reacted thereon,(3S,4R)-trans-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride is formed, at the same time that the tert-butoxycarbonylgroup is deprotected.

The(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride isopropanol solution thus obtained contains impurities insome cases. In this case, the isopropanol solution can be treated withactivated carbon to remove the impurities.

Next, the isopropanol solution is gradually cooled to obtain crystals of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride having good filtration properties.

Usually, isopropanol is incorporated in a content of 8 to 15% by weightin the thus obtained crystals of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride.

The crystals of the(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride are dried, for example, at 80° to 110° C. under reducedpressure to convert the crystals from those having the maximumendothermic peak at a temperature range of 98° to 110° C. to thosehaving the maximum endothermic peak at a temperature range of 118° to132° C. as measured by DSC (differential scanning calorimetry). Thereason why the heating temperature is adjusted to not lower than 80° C.is to rapidly dry isopropanol. The reason why the heating temperature isadjusted to not higher than 110° C. is to avoid melting of the crystals.

The crystals thus converted are composed of anhydrous(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride having an isopropanol content of 0.1 to 5% by weight.

The anhydrous hydrochloride is a compound useful as an antidepressant.

EXAMPLES

The present invention will be described in the following workingexamples, without intending to restrict the scope of the presentinvention thereto.

The anhydrous paroxetine hydrochloride containing isopropanol in thecrystals, which is mentioned in some of the following examples, isdisclosed, for instance, in Japanese Examined Patent Publication No.6-47587 (U.S. Pat. No. 4,721,723) and International Journal ofPharmaceutics, 42, (1988), pp.135-143.

Example 1

A 300-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 150 ml of methanol,33.0 g (183 mmol) of methyl p-fluorocinnamate, 36.3 g (366 mmol) ofmethyl cyanoacetate, and 52.96 g (275 mmol) of 28%-methanol solution ofsodium methylate, while stirring. Thereafter, the resulting mixture washeated to a reflux temperature and kept at the temperature foradditional 90 minutes. The reaction mixture was then concentrated byremoving the solvent using a rotary evaporator.

The concentrated mixture obtained above was poured into a mixture of 150ml of toluene and 200 ml of 5%-aqueous hydrochloric acid. The wholemixture was stirred, and then allowed to stand to separate into organicand aqueous layers, and the aqueous layer was removed therefrom. Theorganic layer was washed with a 100-ml aliquot of a saturated aqueoussodium bicarbonate solution twice, and subsequently washed with 100 mlof water. Thereafter, the organic layer was dried over anhydrous sodiumsulfate, and then the solvent was removed under a reduced pressure usinga rotary evaporator to concentrate the organic layer.

The concentrate was distilled to give dimethyl2-cyano-3-(4-fluorophenyl)glutarate having a boiling point of 168° to170° C. (4 mmHg). The yield was 82.7% based on methyl p-fluorocinnamate.A portion of the product was recrystallized from methanol, to givecrystals having a melting point of 80.2° C.

Example 2

A 300-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 90 ml of methylacetate and 10.5 g (194.4 mmol) of sodium methylate. To the resultingslurry, a mixed solution of 10 ml of methyl acetate and 10.0 g (80.6mmol) of p-fluorobenzaldehyde was added, while stirring, dropwise over aperiod of 30 minutes at a temperature of from 10° to 20° C., and furtherstirred for additional 30 minutes at the same temperature, and then amixed solution of 20 ml of methyl acetate and 11.9 g (120 mmol) ofmethyl cyanoacetate was added dropwise to the above mixture over aperiod of 45 minutes at a temperature of from 10° to 20° C. After thedropwise addition was completed, the resulting mixture was stirred foradditional 13 hours at a temperature of from 57° to 58° C. The resultingmixture was poured into a mixture of 100 ml of toluene and 150 ml of5%-aqueous hydrochloric acid, while stirring, and then allowed to standto separate into organic and aqueous layers, and the aqueous layer wasremoved therefrom. The organic layer was washed with a 100-ml aliquot ofa saturated aqueous sodium bicarbonate solution twice, and subsequentlywashed with 100 ml of water. Thereafter, the organic layer was driedover anhydrous sodium sulfate, and then the solvent was removed under areduced pressure using a rotary evaporator to concentrate the organiclayer.

The concentrate was distilled to give dimethyl2-cyano-3-(4-fluorophenyl)glutarate having a boiling point of from 168°to 170° C. (4 mmHg). The yield was 69.3% based on p-fluorobenzaldehyde.

Example 3

A 500-ml autoclave was charged with 200 ml of methanol, 10.0 g (35.8mmol) of dimethyl 2-cyano-3-(4-fluorophenyl)glutarate prepared in eitherExample 1 or 2, and 1.0 ml of Raney cobalt catalyst, and then hydrogengas was introduced into the autoclave under the conditions of pressure15 to 17 kgf/cm² and reaction temperature 85° to 95° C. to the aboveautoclave. Thereafter, the resulting mixture was stirred for one hourunder the same conditions as given above, and then the obtained mixturewas cooled to a temperature of from 20° to 30° C. Subsequently, afteradjusting the pressure to a normal pressure, the reaction mixture wasfiltered to remove the catalyst, and then the filtrate was concentratedby removing methanol using a rotary evaporator under a reduced pressure,to give 8.97 g of crude crystals of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one.

50 ml of toluene was added to the crude crystals prepared above, andthen the resulting mixture was sufficiently mixed. Thereafter, thecrystals were collected by filtration, and then the crystals wereair-dried, to give 6.55 g of white crystals of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one. The yieldwas 72.8% based on dimethyl 2-cyano-3-(4-fluorophenyl)glutarate.

Example 4

A 200-ml four-necked glass flask equipped with a thermometer and areflux condenser was charged with 50 ml of methanol, 10.0 g (39.8 mmol)of (±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-oneprepared in Example 3, and 1.75 g (43.8 mmol) of sodium hydroxide, andthe mixture was heated while stirring to the reflux temperature, andkept at the reflux temperature for additional four hours. Subsequently,the reaction mixture was cooled to a temperature of from 0° to 10° C.,and 90 ml of 2%-aqueous hydrochloric acid was added thereto, to allowwhite crystals to precipitate.

The crystals were then collected by filtration, and sufficiently washedwith water. Thereafter, the obtained crystals were dried at 60° C. undera reduced pressure, to give 8.26 g of the white crystals of(±)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one. The yield was87.5% based on(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one.

The physical properties of the white crystals prepared in Example 4 wereas follows.

(1) Melting point: 246° C.

(2) IR (KBr) ν(cm⁻¹): 2400-3700, 1710, 1638, 1508, 1208.

(3) ¹H-NMR ((CD₃)₂SO) δ (ppm): 2.32-2.58 (m, 1H), 2.60-2.68 (m, 1H),3.05-3.18 (m, 1H), 3.30-3.58 (m, 3H), 7.19-7.52 (m, 4H), 12.52 (br s,1H).

Example 5

In order to separate the cis isomer contained in the crude crystals of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one preparedin Example 3, about 5 g of the crude crystals were added to about 30 mlof methanol, and the mixture was heated to a reflux temperature. Soonafter, the mixture was gradually cooled using crystals, which remainedin the solution without being completely dissolved, as seed crystals, toprecipitate crystals having a nearly cubic shape. Since needle crystalswould be formed if the crystallization was continued, the cubic crystalswere separated from the solution before the beginning of the formationof the needle crystals. The resulting cubic crystals were recrystallizedagain from methanol, to give(±)-cis-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one.

The physical properties of the cubic crystals prepared above were asfollows.

(1) Melting point: 195.0° to 196.5° C.

(2) IR (nujol mull) ν(cm⁻¹): 3184, 3036, 1736, 1662, 1600, 1510, 1248.

(3) ¹H-NMR (CDCl₃) δ (ppm): 2.72-3.91 (m, 2H), 3.08-3.40 (m, 1H),3.35-3.57 (m, 2H), 3.65 (s, 3H), 3.67-3.82 (m, 1H), 6.51 (br s, 1H),6.95-7.25 (m, 4H).

The solution separated from the cubic crystals was allowed tocrystallize, to give needle crystals of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one, and thenthe crystals were recrystallized from methanol.

The physical properties of the needle crystals prepared above were asfollows.

(1) Melting point: 152.2° to 152.3° C. (Shrinkage of the crystals wasobserved in the tube for measuring a melting point from a temperaturenear 150° C.).

(2) IR (nujol mull) ν(cm⁻¹): 3172, 3036, 1728, 1672, 1604, 1512, 1220.

(3) ¹H-NMR (CDCl₃) δ (ppm): 2.55 (dd, 1H, J=17.8, 10.6), 2.69 (dd, 1H,J=17.8, 5.9), 2.95 (dt, 1H, J=5.3, 9.9), 3.41 (dt, 1H, J=5.9, 10.3),3.45-3.71 (m, 2H), 3.50 (s, 3H), 6.85 (br s, 1H), 6.99-7.25 (m, 4H).

The physical properties of the purified crystals of(±)-trans-4-(4-fluorophenyl)-5-ethoxycarbonylpiperidin-2-one prepared inthe same manner as above were as follows.

(1) Melting point: 143.8° C.

(2) IR (KBr) ν(cm⁻¹): 3180, 3044, 1720, 1662, 1606, 1228, 1206.

(3) ¹H-NMR (CDCl₃) δ (ppm): 0.99 (t, 3H, J=7.3), 2.55 (dd, 2H, J=17.8,10.6), 2.69 (dd, 2H, J=17.8, 5.9), 2.95 (dt, 1H, J=5.3, 9.9), 3.36 (dt,1H, J=5.9, 10.6), 3.48-3.68 (m, 1H), 3.63 (dd, 1H, J=9.9, 10.6),3.87-4.02 (m, 1H), 6.31 (br s, 1H), 6.95-7.22 (m, 4H).

Example 6

50 mg of (±)-cis-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-oneprepared in Example 5 was added to 4 g of methanol. Thereafter, 100 mgof 10%-aqueous sodium hydroxide solution was added to the above mixture,and the resulting mixture was heated and refluxed over a period of threehours. After cooling the reaction mixture, the methanol solution wasconcentrated under a reduced pressure. Subsequently, water was added tothe concentrate, and then the reaction mixture was extracted with ethylacetate to remove a neutral portion. An aqueous hydrochloric acid wasadded to the aqueous layer to make it acidic. Thereafter, the acidicaqueous layer was extracted with ethyl acetate and then concentrated togive about 40 mg of crystals. IR spectroscopy of the crystals which wereprepared by washing the above crystals with a small amount of ethylacetate was found to be identical to that of(±)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one obtained inExample 4.

The same procedures as above were carried out except for adding acatalytic amount of 60%-sodium hydride (dispersion in mineral oil) toobtain sodium methylate solution in place of adding the aqueous sodiumhydroxide solution, and 50 mg of(±)-cis-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one was heatedand refluxed over a period of three hours. After cooling the reactionmixture, the mixture was concentrated under a reduced pressure.Thereafter, water was added to the concentrate, and the obtained mixturewas extracted with ethyl acetate. The extracted neutral part wasconcentrated to give about 40 mg of crystals. IR spectroscopy of thecrystals prepared by washing the above crystals with a small amount ofmethanol was found to be identical to that of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one obtainedin Example 3.

Further, the conversion of methyl esters of the (±)-cis, trans isomersto methyl ester of (±)-trans isomer was carried out by the followingmethod.

Specifically, 30 g of (±)-cis-,trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one and 2.34 g ofa 28% sodium methylate methanol solution were added to 300 ml oftoluene, and the mixture was heated. When the temperature reached 68°C., the (±)-cis-,trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one dissolved. Thesolution was stirred for additional 20 minutes, and gradually cooled andfiltered at 7° C. to give 25.23 g of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one (yield:84.1%).

The obtained crystals of methyl ester of (±)-trans isomer were analyzedby high performance liquid chromatography. The results showed thatmethyl ester of the trans isomer made up 98.75% of the entire products,and substantially no cis isomers were formed, and that the remaining1.25% was made up of trans isomer of carboxylic acid.

Reference Example

The stereostructure (geometric isomers) of the piperidine derivativesrepresented by the formula:

was confirmed as follows.

A 50-ml eggplant-shaped glass flask was charged with about 10 mg oftoluene and 1 g of pyridine. 0.9 g Of(±)-trans-3-hydroxymethyl-4-(4-fluorophenyl)-N-methylpiperidine(hereinafter referred to as “Known Compound A”), which was preparedaccording to the method disclosed in Japanese Unexamined PatentPublication No. 7-138228 was added to and dissolved in the abovemixture. After the mixture was cooled to a temperature of −20° C., amixed solution prepared by dissolving 0.52 g of ethyl chloroformate inabout 5 ml of toluene was added dropwise thereto. The temperature of theresulting mixture was gradually raised to room temperature, and thenallowed to stand at room temperature for about two hours. Thereafter,about 10 ml of water was added to the above mixture, and then themixture was made alkaline by adding aqueous sodium hydroxide solution.The alkaline mixture was allowed to stand to separate into a toluenelayer and an aqueous layer, and the aqueous layer was removed. Thetoluene layer was concentrated by using a rotary evaporator, and theremaining concentrate (hereinafter referred to as “Derivative B”) wasobtained as an oily product. Further, about 5 ml of toluene was againadded to Derivative B, and 1 g of ethyl chloroformate was added to theabove mixture at room temperature. Thereafter, the resulting mixture wasallowed to stand overnight. Subsequently, diluted aqueous hydrochloricacid was added thereto, and the toluene solution was separated therefromas the neutral part. The separated toluene solution was thenconcentrated with a rotary evaporator, to give an oily product of(±)-trans-3-ethoxycarbonyloxymethyl-4-(4-fluorophenyl)-N-ethoxycarbonylpiperidine(hereinafter referred to as “Derivative C”).

On the other hand, a 100-ml four-necked glass flask was charged with 20ml of dry diglyme containing 0.5 g of lithium aluminum hydride, and 0.2g of crystals of(±)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one was addedto the above mixture at room temperature. Thereafter, the resultingmixture was heated to about 100° C. and kept at the temperature for onehour. After cooling the reaction mixture, 10 ml of 28%-aqueous sodiumhydroxide solution was added dropwise to the above mixture. Thereafter,the upper organic layer was separated from the lower layer having a highviscosity by decantation. Subsequently, the lower layer was extractedwith tetrahydrofuran (THF) and the THF part was combined with the upperorganic layer. Further, the solvent was removed, to give 0.2 g of aconcentrate. The resulting concentrate crystallized. The resultingproduct is hereinafter referred to as “Derivative D.”

The melting point of Derivative D, which was prepared separately in thesame manner as above and recrystallized from ethyl acetate was 103.2° to104.0° C.

The reduced product (Derivative D) prepared above was dissolved in 10 mlof pyridine, and the mixture was cooled to −10° C. The solution of 0.5 gof ethyl chloroformate in about 5 ml of toluene was added dropwise tothe cooled mixture. Thereafter, the temperature of the mixture wasallowed to rise to room temperature and kept at room temperature for onehour. Subsequently, water was added to the above mixture, and extractedwith toluene. Thereafter, the toluene extract was concentrated to give0.2 g of an oily product (hereinafter referred to as “Derivative E”). Itwas confirmed by the ¹H-NMR spectroscopy and the high performance liquidchromatography that the obtained product was identical to Derivative C,that is,(±)-trans-3-ethoxycarbonyloxymethyl-4-(4-fluorophenyl)-N-ethoxycarbonylpiperidinewhich was derived from(±)-trans-3-hydroxymethyl-4-(4-fluorophenyl)-N-methylpiperidine preparedby the method disclosed in Japanese Unexamined Patent Publication No.7-138228.

Further, in order to obtain a crystalline compound, a part of DerivativeE was reduced with excess lithium aluminum hydride in the same manner asabove. As a result, a reduced product (hereinafter referred to as“Derivative F”) was obtained. The resulting reduced product was purifiedby silica gel chromatography, and then the part eluted by ethyl acetatecontaining methanol crystallized. The crystals showed the same physicalproperties as the(±)-trans-3-hydroxymethyl-4-(4-fluorophenyl)-N-methylpiperidine (KnownCompound A) prepared by the method disclosed in Japanese UnexaminedPatent Publication No. 7-138228 as follows.

(1) Melting point: 122.5° to 122.9° C.

(2) IR (nujol mull) ν(cm⁻¹): 3144, 1600, 1466, 1450, 1066.

From the above results, it is clear that the stereostructure of thecompound which was designated as “trans isomer” of the piperidinederivatives represented by the preceding formula was identical to thatof the (±)-trans-3-hydroxymethyl-4-(4-fluorophenyl)-N-methylpiperidine.

Example 7

A 3000-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 1560 ml ofisopropanol, 473 ml of ethanol, and 35.58 g (150 mmol) of(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, and themixture was stirred and heated to a temperature of from 70° to 75° C.

While maintaining the temperature of the mixture at a temperature offrom 70° to 75° C., 72.14 g of an ethanol solution containing 34.48 g(151.7 mmol) of R-(+)-N-(4-hydroxyphenylmethyl)phenylethylamine wasadded dropwise to the mixture. The temperature of the mixture was thenkept at a temperature of from 80° to 81° C. for one hour while stirring.Thereafter, the reaction mixture was cooled to 25° C., and stirred foradditional two hours at a temperature of from 20° to 25° C. to allowcrystals to precipitate.

Next, the precipitated crystals were filtered at a temperature of from20° to 25° C., and then the crystals were washed with the mixture of 60ml of isopropanol and 18 ml of ethanol. Thereafter, the crystals weredried under a reduced pressure, to give 32.76 g of crystals, which werea salt of (4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(±)-N-(4-hydroxyphenylmethyl)phenylethylamine. 5 mg Of the abovecrystals was taken, and 5 ml of 3%-aqueous hydrochloric acid was addedthereto, to allow acid decomposition, to give(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Further, the resulting crystals were analyzed by high performance liquidchromatography using a chiral HPLC column. The results showed that thecrystals were composed of 15.5% of the (4S,5R) isomer, and 84.5% of the(4R,5S) isomer, and the optical purity was 69.0%.

Thereafter, 32.76 g of the resulting crystals were added to 350 ml ofmethanol, and the obtained mixture was heated to 65° C. 10 ml Of waterwas added to the resulting mixture at 65° C., and the mixture wasstirred to dissolve the crystals. Subsequently, the reaction mixture wasstirred for additional one hour at a temperature of from 57° to 58° C.,and then 5 mg of seed crystals, which were a salt of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(+)-N-(4-hydroxyphenylmethyl)phenylethylamine was added to the abovemixture, and then the resulting mixture was stirred for additional onehour at a temperature of from 57° to 58° C. Thereafter, the mixture wascooled to 50° C., and then 200 ml of ethyl acetate was added at atemperature of from 47° to 50° C. Further, the mixture was stirred forone hour and 30 minutes at a temperature of from 47° to 50° C.

Further, the mixture was cooled to 25° C., and stirred for additionaltwo hours at a temperature of from 20° to 25° C. to allow crystals toprecipitate. Thereafter, the precipitated crystals were collected byfiltration at a temperature of from 20° to 25° C., and washed with amixed solvent of 40 ml of methanol and 20 ml of ethyl acetate.Subsequently, the washed crystals were dried under a reduced pressure,to give 17.21 g of crystals, which were a salt of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(+)-N-(4-hydroxyphenylmethyl)phenylethylamine. 100 ml Of 3%-aqueoushydrochloric acid was added to 17.21 g of the above crystals, to allowacid decomposition. The crystals were collected by filtration, andwashed with water and then dried under a reduced pressure, to give 8.97g of crystals, which were(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Further, the resulting crystals were analyzed by high performance liquidchromatography using a chiral HPLC column. The results showed that thecrystals were composed of 0.4% of the (4S,5R) isomers, and 99.6% of the(4R,5S) isomers, and the optical purity was 99.2%. The physicalproperties of the resulting crystals were as follows.

(1) Melting point: 236° to 238° C.

(2) IR (nujol mull) ν(cm⁻¹): 3276, 3200, 1704, 1640, 1512, 1404, 1298,1270, 1208, 1194, 1042, 982, 826, 780.

Example 8

A 1000-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 1670 ml ofisopropanol, 30.0 g (126.5 mmol) of(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one, and 35 mlof water, and the mixture was stirred and heated to a temperature offrom 77° to 82° C.

While maintaining the temperature of the mixture at a temperature offrom 77° to 82° C., 90 ml of an isopropanol solution of 29.16 g (128.3mmol) of R-(+)-N-(4-hydroxyphenylmethyl)phenylethylamine was addeddropwise to the mixture prepared above.

Subsequently, 5 mg of seed crystals, which were a salt of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(+)-N-(4-hydroxyphenylmethyl)phenylethylamine were added to the abovemixture at 75° C., and then the resulting mixture was stirred foradditional one hour at a temperature of from 70° to 75° C. Thereafter,the mixture was cooled to 25° C. and then stirred for two hours at atemperature of from 20° to 25° C. to allow crystals to precipitate.Next, the precipitated crystals were collected by filtration at atemperature of from 20° to 25° C., and washed with 30 ml of isopropanol.Thereafter, the washed crystals were dried under a reduced pressure, togive 27.74 g of crystals, which were a salt of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(±)-N-(4-hydroxyphenylmethyl)phenylethylamine.

A part of the above crystals, namely 5 g, was taken, and 5 ml of3%-aqueous hydrochloric acid was added thereto, to allow aciddecomposition, to give crystals of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Further, the resulting crystals were analyzed by high performance liquidchromatography using a chiral HPLC column. The results showed that thecrystals, which were composed of 8.3% of the (4S,5R) isomer, and 91.7%of the (4R,5S) isomer, and the optical purity was 83.49%.

Thereafter, 26.82 g of the resulting crystals were added to 350 ml ofisopropanol, and the obtained mixture was heated to 77° C. 55 ml Ofwater was added to the resulting mixture at 77° C., and the mixture wasstirred to dissolve the crystals. Subsequently, the mixture was stirredfor additional one hour at a temperature of from 77° to 82° C., and then3 mg of seed crystals, which were a salt of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(+)-N-(4-hydroxyphenylmethyl)phenylethylamine was added to the abovemixture. Thereafter, the mixture was cooled to 55° C., and stirred foradditional one hour at a temperature of from 55° to 60° C. Thereafter,the mixture was cooled to 25° C., and stirred for two hours at atemperature of from 20° to 25° C. to allow crystals to precipitate.

Further, the precipitated crystals were collected by filtration at atemperature of from 20° to 25° C., and washed with 20 ml of 85%-aqueousisopropanol. Subsequently, the washed crystals were dried under areduced pressure, to give 16.60 g of crystals, which were a salt of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one andR-(±)-N-(4-hydroxyphenylmethyl)phenylethylamine. 100 ml Of 3%-aqueoushydrochloric acid was added to 16.60 g of the above crystals, and theresulting mixture was stirred at a temperature of 20° to 40° C., toallow acid decomposition. Thereafter, the resulting crystals werecollected by filtration, and washed with water. Subsequently, the washedcrystals were dried under a reduced pressure, to give 8.28 g ofcrystals, which were(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one.

Further, the resulting crystals were analyzed by high performance liquidchromatography using a chiral HPLC column. The results showed that thecrystals were composed of 0.4% of the (4S,5R) isomer, and 99.6% of the(4R,5S) isomer, and the optical purity was 99.2%.

Example 9

A 300-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 100 ml of anhydroustetrahydrofuran and 7.89 g (208.02 mmol) of lithium aluminum hydride,and the slurry mixture was cooled to a temperature of from 5° to 10° C.

To the above slurry, slurry prepared from 16.34 g (69.34 mmol) of(4R,5S)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one and 100 ml oftetrahydrofuran was cautiously added dropwise at a temperature of from10° to 20° C. After the completion of dropwise addition, the resultingmixture was stirred at a temperature of from 10° to 20° C. over a periodof about one hour.

Next, the resulting reaction mixture was gradually heated to a refluxtemperature and stirred for additional two hours or so at the refluxtemperature. Thereafter, the reaction mixture was cooled to atemperature of from 0° to 5° C., and 20% by weight-aqueous sodiumhydroxide solution was dropwise added cautiously.

Thereafter, an upper organic layer and a viscous lower layer wereseparated by decantation. Further, the lower layer was extracted withtetrahydrofuran, and the extract and the organic layer separated bydecantation were combined. Thereafter, the organic layers wereconcentrated, to give a concentrate, which crystallized to give 15.26 gof white crystals.

The physical properties of the obtained crystals were as follows.

(1) Melting point: 81° to 83° C.

(2) IR (nujol mull) ν(cm⁻¹): 3408, 3284, 3176, 1512, 1222, 1026.

(3) ¹H-NMR (CDCl₃) δ (ppm): 7.15 (dd, 2H), 6.97 (dd, 2H), 3.35 (dd, 2H),3.15 (dd, 2H), 2.36-2.71 (m, 6H), 1.55-1.86 (m, 3H).

It can be seen from the above results that the resulting crystals wereconsistent with(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Example 10

(−)-(3S,4R)-4-(4-Fluorophenyl)-3-hydroxymethylpiperidine monohydrate

A 200-ml four-necked glass flask equipped with a thermometer and areflux condenser was charged with 63 ml of toluene and 10.54 g (50.37mmol) of (−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, andthe mixture was warmed and dissolved. 1.13 g (62.71 mmol) Of water wasadded to the above mixture at 50° C. to allow to crystallize.Thereafter, the mixture was kept for one hour at a temperature of from20° to 30° C., and then the crystals were collected by filtration. Theobtained crystals were thoroughly washed with 20 ml of toluene, to givewhite crystals of(−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate.Thereafter, the crystals were dried under a reduced pressure at atemperature of 30° C. or lower, and weighed 10.24 g. The yield was89.45% based on(−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Example 11

The compound(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine wasprepared by reducing(4RS,5SR)-trans-4-(4-fluorophenyl)-5-methoxycarbonylpiperidin-2-one withlithium aluminum hydride in the same manner as in Example 9. 9.0 g (43mmol) Of the above(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, 10.28 g(39.6 mmol) of (2R,3R)-o-chlorotartranilic acid, and 225 ml of waterwere mixed together. Thereafter, the resulting mixture was heated todissolve the mixture at 78° C., and then the mixture was graduallycooled and then a small amount of seed crystals were added at 64° C. Themixture was further gradually cooled, and then the crystals werecollected by filtration at 22° C. The resulting crystals were washedthrice with a 20-ml aliquot of water, and then the washed crystals weredried, to give 8.62 g of the crystals.

In order to further purify the resulting crystals, the crystals wererecrystallized. Specifically, 100 ml of water was added to 8.62 g of thecrystals prepared above, and then the temperature of the mixture wasraised to 78° C., to dissolve the crystals. Thereafter, the mixture wasgradually cooled, to allow crystals to precipitate at about 76° C.Further, the mixture was gradually cooled to a temperature of 20° C.,and then the crystals were collected by filtration. The resultingcrystals were washed thrice with a 10-ml aliquot of water, and then thewashed crystals were dried, to give 7.25 g of crystals.

The physical properties of the obtained crystals were as follows.

(1) Melting point: 119° to 120° C.

(2) IR (nujol mull) ν(cm⁻¹): 3336, 1608, 1524, 1512, 1486, 1440.

Next, 7.25 g of the crystals obtained above were decomposed with about2%-aqueous sodium hydroxide solution, and the resulting mixture wasextracted with ethyl acetate. Thereafter, the extract was concentratedto give 3.48 g of crystals.

The crystals were dissolved in a mixed solvent of an equivolume of ethylacetate and toluene, and then a small amount of water was added thereto,to give 2.72 g of monohydrate crystals.

Next, the resulting crystals were analyzed by high performance liquidchromatography using a chiral HPLC column. The results showed that theoptical purity was 100%. The crystals started melting at 79.5° C., andthey melted at a temperature of 83° to 85° C.

The physical properties of the obtained crystals were as follows.

(1) [α]³⁰ _(D): −35.7 (C=1%-methanol).

(2) IR (nujol mull) ν(cm⁻¹): 3408, 3284, 1510, 1222, 1026.

(3) ¹H-NMR (CDCl₃) δ (ppm): 7.17 (dd, 1H), 7.16 (dd, 1H), 6.99 (dd, 1H),6.99 (t, 1H), 3.39 (dd, 1H), 3.35 (dd, 1H), 3.23 (dd, 1H), 3.15 (d br,1H), 2.70 (dt, 1H), 2.57 (t, 1H), 2.45 (dt, 1H), 1.60-1.90 (m, 3H), 1.70(s, 4H).

Example 12

A 200-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 50 ml of anhydroustetrahydrofuran and 1.51 g (39.8 mmol) of lithium aluminum hydride, andthe slurry mixture was cooled to a temperature of 5° to 10° C.

To the above slurry, slurry prepared from 5.0 g (19.9 mmol) of(4RS,5SR)-trans-5-carboxy-4-(4-fluorophenyl)piperidin-2-one and 50 ml oftetrahydrofuran was dropwise added cautiously at a temperature of from10° to 20° C. After the addition, the resulting mixture was stirred at atemperature of from 10° to 20° C. over a period of about one hour.

Then, the resulting reaction mixture was gradually heated to a refluxtemperature, and kept at the reflux temperature for additional two hoursor so. Thereafter, the reaction mixture was cooled to a temperature offrom 0° to 5° C., and 20% by weight-aqueous sodium hydroxide solutionwas added dropwise thereto cautiously.

Thereafter, an upper organic layer and a viscous lower layer wereseparated by decantation. Further, the lower layer was extracted withtetrahydrofuran, and the extract and the organic layer were combined.Thereafter, the organic layer was concentrated, to give a concentrate,which crystallized to give 4.75 g of white crystals.

The physical properties of the obtained crystals were as follows.

(1) Melting point: 123° to 124° C.

(2) IR (nujol mull) ν(cm⁻¹): 3276, 3244, 3108, 1602, 1506, 1216, 1046,834.

(3) ¹H-NMR (CDCl₃) δ (ppm): 7.15 (dd, 2H), 6.97 (dd, 2H), 3.35 (dd, 2H),3.15 (dd, 2H), 2.36-2.71 (m, 6H), 1.55-1.86 (m, 2H).

It can be seen from the above results that the resulting crystals wereconsistent with(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Example 13

A 300-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 100 ml of toluene, 116ml of 5%-aqueous sodium bicarbonate solution, and 15.26 g of(3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. 11.83 g(69.34 mmol) Of benzyl chloroformate and 116 ml of 5%-aqueous sodiumbicarbonate solution were added to the above mixture at a temperature offrom 10 to 30° C. over a period of about 30 minutes.

The two-phase reaction mixture was stirred at a temperature of from 10°to 30° C. for about one hour. Thereafter, 35%-aqueous hydrochloric acidwas added to the above mixture to make it acidic. The mixture wasallowed to stand to separate into organic and aqueous layers, and theaqueous layer was removed therefrom. The obtained organic layer waswashed with water and then dried over anhydrous magnesium sulfate.Thereafter, the dried organic layer was concentrated, to give 22.94 g ofa slightly yellow, transparent oily product.

The physical properties of the resulting oily product were as follows.

(1) IR (neat) ν(cm⁻¹): 3448, 3032, 1686, 1606, 1512, 1472, 1442, 1222,1126, 1014.

(2) ¹H-NMR (CDCl₃) δ (ppm): 7.30-7.49 (m, 5H), 7.12 (dd, 2H), 6.98 (dd,2H), 5.15 (s, 2H), 4.52 (dd, 1H), 4.28 (s br, 1H), 3.41 (dd, 1H), 3.23(dd, 1H), 2.49-2.81 (m, 3H), 1.63-1.80 (m, 4H).

Example 14

A 200-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 50 ml of toluene, 24ml of 5%-aqueous sodium bicarbonate solution, and 3.0 g of(3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. 2.94 g(17.21 mmol) Of benzyl chloroformate and 29 ml of 5%-aqueous sodiumbicarbonate were added to the above mixture at a temperature of from 10°to 30° C. over a period of about 30 minutes.

The two-phase reaction mixture was stirred at a temperature of from 10°to 30° C. for about one hour. Thereafter, 35%-aqueous hydrochloric acidwas added to the above mixture to make it acidic. The mixture wasallowed to stand to separate into organic and aqueous layers, and theaqueous layer was removed therefrom. The obtained organic layer waswashed with water and then dried over anhydrous magnesium sulfate.Thereafter, the dried organic layer was concentrated, to give 4.92 g ofslightly yellowish white crystals.

The physical properties of the resulting crystals were as follows.

(1) Melting point: 90° to 94° C.

(2) IR (neat) ν(cm⁻¹): 3452, 3032, 2920, 2864, 1690, 1604, 1512, 1472,1278, 1226, 1126, 1064, 834.

(3) ¹H-NMR (CDCl₃) δ (ppm): 7.30-7.49 (m, 5H), 7.12 (dd, 2H), 6.98 (dd,2H), 5.15 (s, 2H), 4.52 (dd, 1H), 4.28 (s br, 1H), 3.41 (dd, 1H), 3.23(dd, 1H), 2.49-2.81 (m, 3H), 1.63-1.80 (m, 4H).

From the above results, it was confirmed that the resulting crystalswere consistent with(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Example 15

A 300-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 100 ml of toluene,22.94 g of(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,and 14.03 g (138.68 mmol) of triethylamine. 9.53 g (83.21 mmol) Ofmethanesulfonyl chloride was added dropwise to the above mixture at atemperature of from 10° to 30° C. over a period of about 30 minutes.

The reaction mixture was stirred at a temperature of from 10° to 30° C.for additional two hours. Thereafter, water was added to the resultingmixture, and the mixture was allowed to stand to separate into organicand aqueous layers, and the aqueous layer was removed therefrom. Theobtained organic layer was washed with water and then dried overanhydrous magnesium sulfate. Thereafter, the dried organic layer wasconcentrated, to give 26.29 g of slightly yellow, transparent oilyproducts.

The physical properties of the oily product, which solidifiedafterwards, were as follows.

(1) Melting point: 90° to 94° C.

(2) IR (neat) ν(cm⁻¹): 1696, 1512, 1472, 1436, 1358, 1224, 1176, 1130.

(3) ¹H-NMR (CDCl₃) δ (ppm): 7.32-7.41 (m, 5H), 7.13 (dd, 2H), 7.02 (dd,2H), 5.17 (s, 2H), 4.32-4.59 (m, 2H), 3.97 (dd, 1H), 3.81 (dd, 1H), 2.87(s, 3H), 2.76-2.91 (m, 2H), 2.59 (m, 1H), 2.06 (m, 1H), 1.66-1.84 (m,2H).

From the above results, it was confirmed that the resulting oily productwas consistent with(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine.

Example 16

A 200-ml four-necked glass flask equipped with a thermometer, a refluxcondenser, and a dropping funnel was charged with 50 ml of toluene, 4.92g of(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,and 1.75 g (21.51 mmol) of pyridine. 1.84 g (16.06 mmol) Ofmethanesulfonyl chloride was added dropwise to the above mixture at atemperature of from 10° to 30° C. over a period of about 30 minutes.

The reaction mixture was stirred at a temperature of from 10° to 30° C.for additional two hours. Thereafter, water was added to the resultingmixture, and the mixture was allowed to stand to separate into organicand aqueous layers, and the aqueous layer was removed therefrom. Theobtained organic layer was washed with water and then dried overanhydrous magnesium sulfate. Thereafter, the dried organic layer wasconcentrated, to give 6.57 g of a slightly yellow, transparent oilyproduct.

The physical properties of the obtained oily product were as follows.

(1) IR (neat) ν(cm⁻¹): 3028, 2936, 1694, 1512, 1470, 1436, 1358, 1278,1228, 1176, 1130, 960, 834.

(2) ¹H-NMR (CDCl3) δ (ppm): 7.32-7.41 (m, 5H), 7.13 (dd, 2H), 7.02 (dd,2H), 5.17 (s, 2H), 4.32-4.59 (m, 2H), 3.97 (dd, 1H), 3.81 (dd, 1H), 2.87(s, 3H), 2.76-2.91 (m, 2H), 2.59 (m, 1H), 2.06 (m, 1H), 1.66-1.84 (m,2H).

From the above results, it was confirmed that the resulting oily productwas consistent with(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine.

Example 17

A 300-ml four-necked glass flask equipped with a thermometer and areflux condenser was charged with 200 ml of methanol, 25.85 g of3,4-methylenedioxyphenol, 26.29 g of(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,and 34.90 g of 28% by weight sodium methylate. The mixture was stirredand then heated to a reflux temperature.

The resulting reaction mixture was refluxed for about 16 hours, and thenmethanol was distilled off. The remaining product was poured into aliquid mixture of 200 ml of toluene and 200 ml of iced water.Thereafter, the toluene layer was separated therefrom, and the aqueouslayer was further extracted with toluene.

Then, the toluene layer which was firstly separated was combined withthe toluene layer obtained by re-extraction, to give a toluene solution.The toluene solution was washed with 5%-aqueous sodium hydroxidesolution, and then with water. The washed toluene solution was driedover anhydrous magnesium sulfate, and the resulting solution wasconcentrated, to give 25.57 g of a brown oily product.

The physical properties of the obtained oily product were as follows.

(1) IR (neat) ν(cm⁻¹): 1704, 1690, 1510, 1502, 1486, 1470, 1276, 1222,1184, 1130, 1038.

(2) ¹H-NMR (CDCl₃) δ (ppm): 7.34-7.39 (m, 5H), 7.11 (dd, 2H), 6.97 (dd,2H), 6.61 (d, 1H), 6.34 (d, 1H), 6.12 (dd, 1H), 5.87 (s, 2H), 5.17 (s,2H), 4.02-4.53 (m, 2H), 3.59 (dd, 1H), 3.44 (dd, 1H), 2.71-3.15 (m, 3H),1.74-2.02 (m, 3H).

From the above results, it was confirmed that the resulting oily productwas consistent with(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

Example 18

A 200-ml four-necked glass flask equipped with a thermometer and areflux condenser was charged with 100 ml of methanol, 4.30 g of3,4-methylenedioxyphenol, 6.57 g of(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,and 6.42 g of 28% by weight sodium methylate. The mixture was stirredand then heated to a reflux temperature.

The resulting reaction mixture was refluxed for about 16 hours, and thenmethanol was distilled off. The remaining product was poured into aliquid mixture of 100 ml of toluene and 100 ml of iced water.Thereafter, the toluene layer was separated therefrom, and the aqueouslayer was further extracted with toluene.

Then, the toluene layer which was firstly separated was combined withthe toluene layer obtained by re-extraction, to give a toluene solution.The toluene solution was washed with 5% aqueous sodium hydroxidesolution, and then with water. The washed toluene solution was driedover anhydrous magnesium sulfate, and the resulting solution wasconcentrated, to give 7.23 g of brown crystals.

The physical properties of the resulting crystals were as follows.

(1) Melting point: 127° to 128° C.

(2) IR (nujol mull) ν(cm⁻¹): 1688, 1504, 1278, 1224, 1192, 1122, 1040,830.

(3) ¹H-NMR (CDCl₃) δ (ppm): 7.34-7.39 (m, 5H), 7.11 (dd, 2H), 6.97 (dd,2H), 6.61 (d, 1H), 6.34 (d, 1H), 6.12 (dd, 1H), 5.87 (s, 2H), 5.17 (s,2H), 4.02-4.53 (m, 2H), 3.59 (dd, 1H), 3.44 (dd, 1H), 2.71-3.15 (m, 3H),1.74-2.02 (m, 3H).

From the above results, it was confirmed that the resulting crystalswere consistent with(3SR,4RS)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

Example 19

A 500-ml autoclave was charged with 200 ml of methanol, 25.57 g (55.2mmol) of(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine,2.80 g of palladium carbon (catalyst), and then hydrogen gas wassupplied to the autoclave under the conditions of pressure 3 to 5kgf/cm² and reaction temperature 40° to 50° C. Thereafter, the resultingmixture was stirred for two hours under the same conditions as givenabove, and then the obtained mixture was cooled to a temperature of from20° to 30° C. Subsequently, after adjusting the pressure to a normalpressure, the reaction mixture was filtered to remove the catalyst, andthen the filtrate was concentrated by removing methanol using a rotaryevaporator under a reduced pressure, to give 17.94 g of a brown oilyproduct(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

The yield of the oily product was 98.7% based on(3S,4R)-trans-1-benzyloxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidine.

Example 20

A 300-ml four-necked glass flask equipped with a thermometer and a gasinlet tube was charged with 17.94 g of(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidineand 200 ml of anhydrous isopropanol under nitrogen gas atmosphere, andthen the mixture was cooled to a temperature of 0° to 5° C. Thereafter,dry hydrogen chloride gas was introduced to the reaction mixture througha gas inlet tube at a temperature of 0° to 5° C. over a period of 45minutes to allow the crystals to precipitate.

The formed crystals were collected by filtration, and washed with 20 mlof anhydrous isopropanol. Thereafter, the washed crystals werethoroughly dried under a reduced pressure, to give 12.73 g of whitecrystals of anhydrous(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride. The yield of the resulting white crystals was 63.9% basedon(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

The physical properties of the resulting crystals were given below,which were consistent with the literature values, so that the resultingcrystals were confirmed to be anhydrous(3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]-piperidinehydrochloride.

(1) Melting point: 116.4° to 118.4° C.

(2) IR (nujol mull) ν(cm⁻¹): 3628, 3420, 1514, 1494, 1220, 1194, 1034,886, 840.

(3) ¹H-NMR (CDCl₃) δ (ppm): 9.86 (s br, 2H), 7.21 (dd, 2H), 6.99 (dd,2H), 6.62 (d, 1H), 6.32 (d, 1H), 6.11 (dd, 1H), 5.88 (s, 2H), 3.71 (m,2H), 3.60 (dd, 1H), 3.48 (dd, 1H), 2.86-3.21 (m, 3H), 2.66-2.96 (m, 1H),2.39 (ddd, 1H), 2.03 (d br, 1H).

Example 21

Preparation of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine

A 500-ml four-necked glass flask equipped with a thermometer was chargedwith 127.2 ml of toluene and 25.43 g (111.89 mmol) of(−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine monohydrate,and the mixture was homogeneously stirred at a temperature of from 20°to 30° C. Thereafter, while stirring, 24.42 g (111.89 mmol) ofdi-tert-butyl dicarbonate was added dropwise to the mixture at atemperature of from 20° to 30° C. Subsequently, the reaction mixture wasstirred for 30 minutes at a temperature of from 20° to 30° C., and thenthe solvent was removed under a reduced pressure using a rotaryevaporator, to give a concentrate containing a crude oil product of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.The yield was 102.61% based on(−)-(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Example 22

Preparation of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine

A 500-ml four-necked glass flask equipped with a thermometer was chargedwith 113.9 ml of toluene, 48.69 g (100 mmol) of(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidineo-chloro-L-tartranic acid monohydrate, 91.9 ml of water and 22.92 g (105mmol) of di-tert-butyl dicarbonate, and then the mixture was stirred ata temprature of from 20° to 30° C. Thereafter, while stirring, 17.6 g(110 mmol) of 25% aqueous sodium hydroxide solution was added dropwiseto the mixture at a temperature of 20° to 50° C. The reaction solutionwas heated to a temperature of 45° to 55° C. and stirred at the sametemperature for 30 minutes, and then the aqueous layer was removedtherefrom. Further, 34.1 g of water was added to the organic layer, andthe organic layer was washed with water, and then the aqueous layer wasremoved therefrom. The organic layer was concentrated by removing thesolvent using a rotary evaporator under a reduced pressure, to give aconcentrate containing a crude oil product of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidinein the amount of 32.14 g. The yield was 103.89% based on(3S,4R)-4-(4-fluorophenyl)-3-hydroxymethylpiperidineo-chloro-L-tartranic acid monohydrate.

Example 23

Preparation of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine

A 500-ml four-necked glass flask equipped with a thermometer was chargedwith 153.5 ml of toluene and 23.61 g (76.31 mmol) of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine,and 8.49 g (83.90 mmol) of triethylamine was added to the above mixture,and then the mixture was stirred at a temperature of from 10° to 30° C.Thereafter, while stirring, 8.74 g (76.30 mmol) of methanesulfonylchloride was added dropwise to the mixture at a temperature of from 10°to 20° C. Thereafter, the reaction mixture was stirred for additionalfour hours at a temperature of 20° to 30° C., and 85.7 ml of water wasadded to the resulting reaction mixture, and then the aqueous layer wasremoved therefrom. Further, the organic layer was washed with brine byadding 85.7 ml of water and 4.3 g of sodium chloride, and then separatedto remove the aqueous layer therefrom. Thereafter, the organic layer wasconcentrated by removing the solvent under a reduced pressure using arotary evaporator, to give a concentrate containing a crude oil productof(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine.The yield was 98.62% based on(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine.

Example 24

Preparation of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidine

A 500-ml four-necked glass flask equipped with a thermometer and areflux condenser was charged with 19.44 g (50.17 mmol) of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine,117 ml of toluene, 8.32 g (60.24 mmol) of sesamol, and 10.65 g (55.20mmol) of a 28%-sodium methylate methanol solution, while stirring, undernitrogen gas atmosphere. Thereafter, the resulting mixture was heated toa reflux temperature, and kept at the above reflux temperature foradditional 6 to 18 hours, and cooled. Then, the reaction mixture wassufficiently washed with an alkaline aqueous solution by adding 117 mlof water, 5.85 g of sodium chloride, and 2.0 g of 99%-flaky sodiumhydroxide to the resulting mixture, and then the aqueous layer wasremoved. Thereafter, the organic layer was concentrated under a reducedpressure using a rotary evaporator, to give a concentrate containing acrude oil product of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

The yield was 98.06% based on(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-methylsulfonyloxymethylpiperidine.

The physical properties of the resulting compound were as follows.

(1) IR (paste) ν(cm⁻¹): 1682, 1510, 1488, 1216, 1184.

(2) ¹H-NMR (CDCl₃) δ (ppm): 7.12 (m, 2H), 6.97 (m, 2H), 6.62 (d, 1H),6.34 (d, 1H), 6.13 (dd, 1H), 5.87 (s, 2H), 3.60 (dd, 1H), 3.44 (dd, 1H),2.63-2.88 (m, 3H), 2.01 (m, 1H), 1.72 (m, 1H), 1.50 (s, 9H).

Example 25

Preparation of(−)-(3S,4R)-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)-oxymethyl]piperidinehydrochloride

A 100 ml four-necked glass flask equipped with a thermometer and areflux condenser was charged with 75.7 ml of isopropanol and 9.15 g(21.30 mmol) of(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[3,4-methylenedioxyphenyl)oxymethyl]piperidine,and the mixture was dissolved therein under nitrogen gas atmosphere.Thereafter, 9.70 g (53.21 mmol calculated as hydrochloric acid) of a20%-isopropanol solution of hydrochloric acid was added dropwise to theabove reaction mixture at a temperature of from 20° to 30° C., andstirred at a temperature of from 20° to 30° C. for one hour.Subsequently, the resulting mixture was heated to a reflux temperature.After stirring the reaction mixture at the above reflux temperature foradditional two hours, the reaction mixture was cooled, and then a smallamount of seed crystals of(−)-(3S,4R)-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride containing isopropanol was added thereto, to afford acrystalline product. After sufficient crystallization, the reactionmixture was cooled to a temperature of from 0° to 5° C., and then thecooled mixture was kept at a temperature of from 0° to 5° C. for onehour. The resulting crystals were collected by filtration, and thecrystals were sufficiently washed with isopropanol, to give whitecrystals, which were(−)-(3S,4R)-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinehydrochloride. The resulting crystals were dried under a reducedpressure at 90° C., to give 6.17 g of a product.

The yield was 79.17% based on(3S,4R)-1-tert-butoxycarbonyl-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidine.

The above crystals contained isopropanol in an amount of 2.51% byweight.

Experimental Example

A four-necked glass flask was charged with 223.2 g (0.6777 mol) of(3S,4R)-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidineand 2150 ml of isopropanol, and 135.9 g (0.7454 mol) of a 20%isopropanol solution of HCl was added dropwise to the above mixture overa period of 10 minutes at a temperature of from 50° to 60° C.

Next, 11.21 g of activated carbon was added to the mixture to decolorizeand the mixture was stirred over a period of 15 minutes at a temperatureof from 60° to 70° C. Thereafter, the resulting mixture was filtered toremove the activated carbon, and then washed with 225 ml of hotisopropanol of a temperature of from 70° to 80° C. As a result, thesolution could be substantially decolorized.

The filtrate was cooled to a temperature of from 45° to 50° C., and thenseed crystals were added thereto, to allow crystals to precipitate.Thereafter, the slurry of crystals was kept for one hour at atemperature of from 0° to 5° C. Subsequently, the crystals werecollected by filtration, and then the obtained crystals were washed with640 ml of cold isopropanol of a temperature of from about 0° to about 5°C. The washed crystals were dried under a reduced pressure at 70° C., togive 209.4 g (0.5117 mol) of white paroxetine hydrochloride containing10.6% of isopropanol.

Further, 180.3 g (0.4406 mol) of the paroxetine hydrochloride was driedunder a reduced pressure, to give 157.7 g (0.4216 mol) of whiteparoxetine hydrochloride containing 2.2% of isopropanol.

With the paroxetine hydrochloride containing 10.6% of isopropanol, theprofile between the drying temperature and the residual amount ofisopropanol was examined. The results are shown in Table 1.

TABLE 1 Residual Amount of Isopropanol (% by weight) Drying DryingDrying Drying Drying Drying Period Temp. Temp. Temp. Temp. Temp. (Hr.)(70° C.) (80° C.) (90° C.) (100° C.) (110° C.) 0 (10.58) (10.58) (10.58)(10.58) 3 10.58 8 0.24 10 9.96 12 8.72 0.50 0.20 14 4.25 24 6.80 0.390.13 26 2.34 32 2.20 48 4.44 72 9.90 4.09 96 3.73 168 2.44

It can be seen from Table 1 that by the combinations of the dryingtemperatures ranging from 80° to 110° C. and the drying time course of168 hours, the residual amount of isopropanol can be controlled within arange of from 0.1 to 5%.

As explained above, according to the present invention, a compoundhighly useful as an intermediate for the preparation of paroxetine canbe advantageously prepared in a simple manner.

Also, paroxetine hydrochlorides and anhydrous crystals can be preparedin a simple manner from the above compound.

The present invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

What is claimed is:
 1. A method for preparing a crystallinehydrochloride of (3S,4R)-trans-4-(4-fluorophenyl)-3-[(3,4-methylenedioxyphenyl)oxymethyl]piperidinecontaining isopropanol, comprising the steps of: (A) reacting4-fluorobenzaldehyde with acetic acid ester represented by the formula:CH₃COOR⁵ wherein R⁵ is an alkyl group having 1 to 4 carbon atoms to givea 4-fluorocinnamic acid ester, (B) reacting the resulting4-fluorocinnamic acid ester with a cyanoacetic acid ester represented bythe formula: NC—CH₂—CO₂—R⁶ wherein R⁶ is an alkyl group having 1 to 4carbon atoms to give a glutaric acid ester compound represented by theformula (X):

wherein R⁵ and R⁶ are as defined above, (C) reducing the resultingglutaric acid ester compound to give (±)-cis,trans-4-(4-fluorophenyl)-5-alkoxycarbonyl-piperidine-2-one representedby the formula (IX):

wherein R⁵ is as defined above, (D) transforming the (±)-cis,trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidine-2-one represented bythe formula (IX) in the presence of a base to give (4RS,5SR)-trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidine-2-one; reducingthe (4RS, 5SR)-trans-4-(4-fluorophenyl)-5-alkoxycarbonylpiperidine-2-onewith a metal hydride compound to give (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethyl piperidine, and opticallyresolving the (3SR,4RS)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine to give (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented bythe formula (II):

(E) reacting the (3S,4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine represented bythe formula (II) with a protecting agent represented by the formula(III):

wherein R³ is a tert-butyl group, and Y is a tert-butoxycarbonyloxygroup, to give a carbamate compound represented by the formula (IV):

wherein R³ is as defined above, (F) reacting said carbamate compoundwith sulfonic acid chloride represented by the formula (V):

wherein R⁴ is an alkyl group having 1 to 2 carbon atoms or a phenylgroup which may have a methyl group at the 4-position, to give asulfonic acid ester represented by the formula (VI):

wherein R³ and R⁴ are as defined above; (G) reacting said sulfonic acidester with 3,4-methylenedioxyphenol under basic conditions, to give apiperidine compound represented by the formula (VII):

wherein R³ is as defined above; and (H) treating said piperidinecompound with hydrogen chloride in isopropanol.
 2. The method accordingto claim 1, wherein the reducing step of (C) is carried out by catalytichydrogenation.
 3. The method according to claim 1, wherein the opticalresolving in the step (D) is carried out with (2R,3R)-o-chlorotartranilic acid.
 4. The method according to claim 1,wherein said sulfonic acid chloride is methanesulfonyl chloride.